Lung Cancer Research:From Prevention to Cure!
Ravi Salgia, M.D, Ph.D Ravi Salgia, M.D, Ph.D
Associate Professor of MedicineAssociate Professor of MedicineDirector, Thoracic Oncology Research ProgramDirector, Thoracic Oncology Research Program
Department of MedicineDepartment of MedicineSection of Hematology/OncologySection of Hematology/Oncology
University of Chicago Cancer Research CenterUniversity of Chicago Cancer Research Center
University of ChicagoUniversity of ChicagoPritzker School of MedicinePritzker School of Medicine
Introduction Lung cancer is one of the most common
cancer worldwide. There will be >170,000 diagnosed cases
of lung cancer in 2006. There will be >160,000 deaths from lung
cancer in 2006. About 75-80% of lung cancers are
associated with smoking However, over 50% have stopped
smoking. AND over 15-20% NEVERsmoked.
Lung Cancer: More ResearchNeeded Every three minutes someone is
diagnosed with lung cancer Men have a lifetime risk of 1 in 13 and
women 1 in 17 In 2003, the federal government spent
$14,045/breast cancer death,$10,761/prostate cancer death,$1,632/lung cancer death
Diagnosis of Lung Cancer
Signs and SymptomsCough (especially with blood), fevers, weight
loss, facial swelling, pain, etc. Scans
CXRAYCTPET
TestsBloodBronchoscopiesBiopsies
Next Generation Scanners CanSee a Pinhead-Size Spot
Prototypes capableof 1mm resolution
Scanning within abreath
Look deep insidethe lung
Kiessling et al, Nature Med online, 9/7/2004
Image Courtesy of Dianna Cody, MDAH
How Do You Study Lung Cancer?
Microscopy Cellular biology Genetics Proteomics
Lung Cancer—Anatomy
Silverberg, 3rd ed
Lung Cancer- Histology
SCLC
ADENOCARCINOMA SQUAMOUS CELL CARCINOMA
LARGE CELL CARCINOMA BAC
NSCLC
Normal Cells
Cancer Cells
EGFR
MET
ErbB-2
Tyrosine kinase domain
Tyrosine kinase domain
SEMA Tyrosine kinase domainJMPSI domain
Mutations in the EGFR, erbB-2 and MET Gene in Lung Cancer
L861QL858R
R776CdelL747-T751insS
delS752-I759
delL747-P753insS
L755Pins774(AYVM)
ins779(VGS)
delE746-A750
S1058P*R988C
G719C
*T1010I
*IVS 13-(52-53)insCT
del 141bp2942-3082
*E168DN375S
S323GL229F
Laser Microdissection-AssistedSequencing
Before During After
EGFR Expressing AdenocarcinomaNSCLC
EGFR
EGFR Mutations in LCM-Tumor Cells (Hilar LN)
Lumbar Puncture: CSF
CSF
NSCLC
Leukocyte
EGFR Mutations in LCM-Tumor Cells(CSF)
Tumor Tissue Microarray
University of Chicago TMA
Biological Targets for CancerTherapy
Tumor Cell
4. Proteasome, Heat Shock Proteins
1
2
345
6
1. Growth factors andgrowth-factor receptorsHER family, c-Met, VEGF/R, c-kit/SCFR
2. Signal-transduction pathwaysRas, raf, MAPK, MEK, ERK,protein kinase C, PI3K
3. Tumor-associatedantigens/markersGangliosides, CEA, MAGE,CD20, CD226. Extracellular matrix/
angiogenic pathwaysMMPs, VEGF, integrins
5. Cell-survival pathwaysCyclin-dependent kinases,mTOR, cGMP, COX-2, p53, Bcl-2
Therapy for Lung Cancer
Surgery Radiation Therapy Chemotherapy Novel Targeted Therapies
Breakthroughs inthe Treatment ofLung Cancer
Adjuvant Therapy for LungCancer Adjuvant therapy – treatment (e.g.
chemotherapy) after surgery to eradicatemicroscopic residual cancer and preventcancer recurrence
5 Large Studies have shown that AdjuvantChemotherapy can increase cure rate inlung cancer
Drugs Recently Approved for AdvancedNon-Small Cell Lung Cancer
Gefitinib (Iressa) – May 2003 (withdrawnJuly 2005)
Pemetrexed (ALIMTA) – February 2004
Erlotinib (Tarceva) – November 2004
Bevacizumab (Avastin) – October 2006
Pemetrexed
Chemotherapy approved for mesotheliomaand lung cancer
Given IV, usually with platinum Does not cause hair loss Vitamin B12 and folic acid need to be
taken with it.
Erlotinib
Oral EGFR tyrosine kinase inhibitors Have activity in non-small-cell lung cancer (~10-
15% of tumors will shrink; ~30-40% will bestable)
Tarceva improves survival in patients withmetastatic disease that have failed first-linechemotherapy
Occasional dramatic and durable tumorresponses are seen
Tarceva
Targets a receptorfound in lung cancer
Taken by mouth Less side effects (no
hair loss or nausea) Rash and diarrhea
seen
How Does Tarceva Work?
Tumor Shrinkage with Tarceva:
Normal and Tumor VasculatureTumor Blood VesselsNormal Blood Vessels
Reduced integrinexpression1
Less dependent on cellsurvival factors2
Maturation factors present(eg, Ang-1)1
.... ..... Less permeable3
.... .....
Supporting cellspresent2
Growth and survivalfactors (eg, VEGF, bFGF)
present2
........................
.... ..... .... .....
........................
.... .....
........................
........................
........................
Leaky3
Preferentialexpression ofαvβ3, αvβ5,and α5β1integrins1
Fewer supportingcells2
1. Griffioen and Molema. Pharmacol Rev. 2000;52:237.2. Blau and Banfi. Nat Med. 2001;7:532.3. Jain. Nat Med. 2001;7:987.
– monoclonal antibody - small molecule– binds VEGF (ligand) - inhibits VEGFR2
(receptor), c-Raf, etc.- intravenous QOW - oral twice daily-bleeding, arterial thrombi, - skin toxicities, alopecia,proteinuria diarrhea
BEVACIZUMAB SORAFENIB
Future for Lung Cancer—withEffective Research
In the future, we will have routine: Scans Blood tests Bronchoscopy/Sputum tests Family screens
In the future, we will have better: Prevention Diagnosis Ability Surgery Radiation Therapy Chemotherapy (Including Novel Therapies)
“If you wantto changethe world,be thatchange.”
--Mahatma Gandhi